Extant drug treatments for pain, which is the most salient symptom of inflammatory arthritis, are limited by insufficient efficacy and negative side effects that range from gastrointestinal irritation to addiction. Cannabis has been used for millennia for its analgesic and anti-inflammatory properties. Although, the psychoactive effects and abuse potential have limited the broad use of cannabis, recent research has uncovered an endogenous cannabinoid (i.e., endocannabinoid) receptor system that affects a broad range of health outcomes, including liver function, hunger, pain, anxiety, depression, and inflammation. The most studied endocannabinoid is anandamide (N- arachidonoylethanolamine), which is primarily metabolized in vivo by fatty acid amide hydrolase (FAAH). Pharmacological inhibition or genetic deletion of FAAH increases tissue levels of anandamide, reducing pain and inflammation, absent the psychomimetic side effects of Cannabis. In other words, FAAH inhibition reduced the pain response, but there are no observed changes in locomotor activity, muscle coordination, or cognitive function. We have recently reported that FAAH inhibition or genetic deletion of FAAH significantly attenuates pain and joint inflammation caused by the collagen-induced arthritis (CIA) model of inflammatory arthritis. We have also reported that FAAH inhibition augments the analgesic potency of the non-steroidal anti-inflammatory drug (NSAID) diclofenac sodium in acute inflammatory pain. Co-administration of the FAAH inhibitor and NSAID is hypothesized to augment reductions in pain and inflammation in mice subjected to collagen-induced arthritis. We propose to determine if this drug interaction is additive or synergistic in attenuating pain (Aim 1) and joint inflammation (Aim 2). We also propose to determine which inflammatory factors (i.e., cytokines, chemokines, and prostaglandins) are critical in FAAH/NSAID modulation of joint inflammation, as reported in our preliminary data. We have also reported that FAAH inhibition blocks the development of gastric lesions caused by non-steroidal anti-inflammatory drugs. Thus, it may be possible not only to gain increased analgesic and anti-inflammatory efficacy by administering low doses of either drug, but also to avoid the side effects of high dose NSAIDs. In addition to having an important positive impact on patients, these data will inform research and development of next generation analgesic, anti-inflammatory treatments for inflammatory arthritis.